Possible role of local hypoxia in the de novo formation of dural and osteodural arteriovenous fistulas after encephalitis. A case report.

A rare case of de novo formation of dural and osteodural arteriovenous fistulas after encephalitis is presented. We review and discuss the etiological angiogenetic factors and processes in intracranial dural arteriovenous fistulas formation. Local tissue hypoxia may have played a role in the initial step causing sprouting angiogenesis as the main pathogenesis of DAVFs formation.

Facial myokymia associated with an isolated lesion of the facial nucleus.

We report on a patient with transient facial myokymia. He had an isolated lesion of the right facial nucleus in the pontine tegmentum. Facial myokymia is a rare symptom and its pathogenesis is not known. Our case had a very localized lesion and we attempted to determine the case of the facial myokymia.

A large Japanese family with Machado-Joseph disease: clinical and genetic analysis.

We report clinical and genetic studies on a large Japanese family with Machado-Joseph disease (MJD), in which various different clinical phenotypes were seen in the same family, i.e., cerebellar ataxia type, severe amyotrophy type, and young-onset parkinsonism type. In addition, patients with very mild symptoms (formes frustes) were encountered. The expansion of the CAG repeat at the MJD locus ranged from 64 to 71 in 7 affected and 4 presymptomatic individuals. In our family, no clear inverse correlation was noted between the length of CAG-expansion and the age of onset, or the clinical phenotypes. Hyporeflexia was a common manifestation seen in 5 patients. It has been reported that the presence of peripheral neuropathy in MJD is associated with smaller increase in the CAG repeats; findings in our family conform with this observation.

Molecular genetic analysis of a novel Parkin gene in Japanese families with autosomal recessive juvenile parkinsonism: evidence for variable homozygous deletions in the Parkin gene in affected individuals.

Autosomal recessive juvenile parkinsonism (AR-JP) is a distinct clinical and genetic entity characterized by selective degeneration of nigral dopaminergic neurons and young-onset parkinsonism with remarkable response to levodopa. Recently, we mapped the gene locus for AR-JP to chromosome 6q25.2-q27 by linkage analysis and we identified a novel large gene, Parkin, consisting of 12 exons from this region; mutations of this gene were found to be the cause of AR-JP in two families. Now we report results of extensive molecular analysis on 34 affected individuals from 18 unrelated families with AR-JP. We found four different homozygous intragenic deletional mutations, involving exons 3 to 4, exon 3, exon 4, and exon 5 in 10 families (17 affected individuals). In addition to the exonic deletions, we identified a novel one-base deletion involving exon 5 in two families (2 affected individuals). All mutations so far found were deletional types in which large exonic deletion accounted for 50% (17 of 34) and the one-base deletion accounted for 6% (2/34); in the remaining, no homozygous mutations were found in the coding regions. Our findings indicate that loss of function of the Parkin protein results in the clinical phenotype of AR-JP and that subregions between introns 2 and 5 of the Parkin gene are mutational hot spots.

Point mutations (Thr240Arg and Gln311Stop) [correction of Thr240Arg and Ala311Stop] in the Parkin gene.

Autosomal recessive juvenile parkinsonism (AR-JP) is a distinct clinical and genetic entity characterized by selective degeneration of nigral neurons. Recently, the parkin gene responsible for AR-JP has been identified. To date, we found two different deletional mutations including single and multiple exonic deletions. In the present study, we identified two types of point mutations (Thr240Arg and Gln311Stop) involving exons 6 and 8 in the parkin gene of the AR-JP patients from two Turkish families. This is the first report on point mutations for the parkin gene. Furthermore, the Thr240Arg mutation was located on a consensus sequence for the site of phosphorylation by casein kinase II. Identification of its mutation provides an important clue as to the role of the Parkin protein in degeneration of the substantia nigra in the brain of AR-JP patients.

A microdeletion of D6S305 in a family of autosomal recessive juvenile parkinsonism (PARK2).

A gene for autosomal recessive juvenile parkinsonism (ARJP; HGMW-approved symbol PARK2; MIM 600116) has recently been mapped to a 17-cM interval on chromosome 6q25.2-q27. We here report an inbred family with ARJP showing a perfect cosegregation with null allele for D6S305, which is a marker within the ARJP locus. We assigned the deletion within an interval between D6S1937 and AFMa155td9, which are 0 cM apart from each other and located on a single YAC clone. Two possibilities should be evaluated: (1) the deletion is polymorphic and linked to ARJP and (2) the deletion is pathogenic and contains both D6S305 and the ARJP gene (or a part of it). An exon search in a deleted segment or in the relatively small-sized genomic clones harboring D6S305 may enormously facilitate the cloning procedure of the ARJP gene.

Mn SOD activity and protein in a patient with chromosome 6-linked autosomal recessive parkinsonism in comparison with Parkinson's disease and control.

We report Mn superoxide dismutase (SOD) protein and activity in a patient with familial autosomal recessive Lewy body-negative parkinsonism in comparison with patients with sporadic Parkinson's disease (PD) and controls. We recently proved linkage of this family with markers of chromosome 6 at 6q25.2-27, which included the Mn SOD gene. We used a novel polymorphic mutation at -9 position of the signal peptide of the Mn SOD precursor protein, which caused valine to alanine substitution. All the affected members of this family showed homozygosity for alanine, whereas nonaffected members, sporadic PD patients, and the control subjects studied showed either heterozygosity of alanine and valine or homozygosity of valine. The Mn SOD activity of this familial patient was the highest among the PD patients and the control subjects studied, and an abundant expression of Mn SOD was found in the substantia nigra. The molecular weight of Mn SOD protein by Western blotting of this patient was essentially similar to that of PD patients and the control subjects. High Mn SOD activity may constitute a genetic risk factor in this familial patient. The difference in the signal peptide sequence may affect the expression of Mn SOD within mitochondria; however, it is unlikely that loss of function type Mn SOD mutation is the cause of this familial parkinsonism. Mn SOD in sporadic PD patients was similar to that in controls.

An immunohistochemical study on manganese superoxide dismutase in Parkinson's disease.

We report an immunohistochemical study on manganese superoxide dismutase (Mn SOD) in Parkinson's disease (PD) patients and age-matched control subjects. Overall appearance of immunostaining intensity of nigral neurons did not differ significantly between the PD patients and the control subjects. However, when the immunostaining intensity of each neuron was semiquantitatively analyzed, both very intensely stained (more than normal) neurons as well as neurons stained only weakly were more frequently detected in the lateral part than in the medial and the central parts of the substantia nigra in PD patients. As a result, the proportion of normally stained neurons was significantly smaller in the lateral part of the substantia nigra in PD patients; however, the overall distribution of the neurons among the three rating grades for immunostaining did not differ significantly. The immunostaining intensity of the neuropils in the medial and the central part of the substantia nigra tended to be more intense in PD patients than in the control subjects. Our results suggest up-regulation of Mn SOD mainly in the dendritic processes of the less involved nigral neurons.

[A 85-year-old woman with the onset of progressive gait disturbance at 80 years of the age].

We report a 85-year-old woman who had an onset of gait disturbance at 80 years of the age. She had a dizzy spell when she was 80-year-old. She was evaluated at another hospital where paroxysmal tachycardia and sinus arrest lasting as long as 5.8 seconds were found. She was diagnosed as having sick sinus syndrome and a pace maker was inserted. She had a gradual onset of disturbance of gait shortly after the above dizzy spell. She became unable to walk fast and her steps became small. Neurologic examination at age 83 revealed small step gait with freezing episodes. Retropulsion was present. No motor weakness or origidity was noted. She had no tremor. Mentally she was alert and sound. Cranial nerves were essentially normal. Cranial CT scan revealed slight diffuse low density change in the bilateral cerebral white matter. She was treated with amantadine HCI and levodopa with carbidopa. Her gait and balance showed some improvement. She developed pneumonia and worsening of her gait when she was 85 years of the age, and she was admitted again to our hospital. She was mentally alert and sound but she showed marked freezing of gait with loss of postural reflex; she would have fallen down unless supported upon standing. Cranial nerves were again essentially normal. Her hospital course was complicated by pneumonia, DIC, and renal failure. She expired suddenly on the 10th day of her last admission. She was discussed in a neurological CPC and the chief discussant arrived at the conclusion that the patient had vascular parkinsonism due to lacunar state. However, paucity of vascular changes in her CT scan remained as a question. Other participants thought that she had nigral cell loss secondary to her aging and circulatory disturbance which would have been caused by her sick sinus syndrome. Post-mortem examination revealed marked loss of nigral pigmented cells; the cell loss was diffusely seen in the substantia nigra. Neurofibrillary tangles were seen in the remaining neurons. In addition, gliosis was noted in the globus pallidus and the subthalamic nucleus, however, neuronal loss was very mild in those nuclei. In the superior colliculus, neuronal loss was mild, however, gliosis was seen. No clear neuronal loss was observed in the locus coeruleus, however, Lewy bodies were seen in the remaining neurons. Furthermore, Lewy bodies were also found in the substantia sigra. It was thought that she had progressive supranuclear play (PSP). Question was whether or not she was complicated by Parkinson's disease. Clinically, she had no rigidity or tremor. Pathologically, locus coeruleus did not show neuronal loss. Therefore, incidental Lewy body disease was raised as a possibility. Finally, it should be pointed out that she had no oculomotor disturbance or dementia, yet she had PSP. Her clinical features were those of pure akinesia. Pathologic changes were also relatively mild except for those in the substantia nigra. Possibility of post-encephalitic parkinsonism without encephalitis was also discussed, however, over all distribution of her pathologic changes was more consistent with PSP.

[A 70-year-old man with a progressive gait disturbance and gaze palsy].

We report a 70-year-old man with progressive gait disturbance and gaze palsy. The patient was well until summer of 1991 when he was 66-year-old, when he noted a gradual onset of difficulty in gait and looking downward. He was evaluated in our hospital in May, 1994 when he was 69-year-old. On admission, he was alert but markedly demented with disorientation and memory loss. Constructional apraxia and dressing apraxia were noted. He had difficulty in gaze to all directions; he could move his eyes only 20% of the normal range. Oculocephalic response was retained. He had small voice and some dysphagia. Other cranial nerves were unremarkable. He could not walk unsupported. Marked retropulsion was noted in which he would fell down spontaneously upon standing unless supported. Moderate to marked rigidity was noted in the neck, trunk, and in the legs, however, in the upper extremities, rigidity was only mild. No tremor was noted. Deep reflexes were symmetrically exaggerated with ankle clonus bilaterally. Plantar response was flexor. Sensation was intact. Routine laboratory tests were unremarkable, however, his cranial MRI showed moderate to marked fronto-temporal atrophy and moderate midbrain and pontine tegmental atrophy. The third ventricle was markedly dilated. He was discharged for out patient care, however, his dysphagia had become progressively worse, and he suffered from frequent bouts of pneumonia. He was admitted to our service on October 17, 1994. His neurologic examination was essentially similar except that he showed more advanced dementia. He was still able to stand with support. Gastrostomy was placed on October 25. Post-operative course was unremarkable. He was discharged on November 1. His motor disturbance showed gradual deterioration, and by the May of 1995, he became bed-ridden, and was admitted to another hospital on May 30, 1995. He was almost totally unable to move his eyes, but oculocephalic response was still elicited. Marked truncal and limb rigidity were noted. He vomited coffee-ground substance on October 31, 1995, and developed hypotension. The subsequent course was complicated by pneumonia and he expired on November 24. The patient was discussed in a neurological CPC. Majority of the participants thought that the patient had progressive supranuclear palsy, but some participants thought that the patient had corticobasal degeneration because cortical atrophy was so marked. Post mortem examination revealed atrophy of the frontal and parietal lobe. The brain stem was atrophic particularly in the tegmental area including the midbrain. The substantia nigra showed marked neuronal loss and globose type neurofibrillary tangles in the remaining neurons. The neurons in the locus coeruleus was well retained, however neurofibrillary tangles were seen. In addition, the cerebellar dentate nucleus, the inferior olivary nucleus, and the internal globus pallidus showed marked neuronal loss and neurofibrillary degeneration. In the frontal cortex, although macroscopic examination showed some atrophy, microscopic examination failed to show neuronal loss or gliosis. The pathologic findings were consistent with the diagnosis of progressive supranuclear palsy.

Catechol-O-methyltransferase genotype and susceptibility to Parkinson's disease in Japan. Short communication.

We report -108Met/Val polymorphism of the COMT gene in Japanese patients with Parkinson's disease (PD). The allele frequency for -108Val was higher in PD patients compared with controls, although the differences did not reach the statistical significance. However, the frequency of -108Val homozygotes was significantly higher in PD patients (56.8%) than in control subjects (44.2%), and heterozygotes of -108Met/Val were less in PD. COMT gene polymorphism may constitute a genetic risk factor for PD among Japanese.

Immunohistochemical detection of 4-hydroxynonenal protein adducts in Parkinson disease.

There is growing evidence that oxidative stress and mitochondrial respiratory failure with attendant decrease in energy output are implicated in nigral neuronal death in Parkinson disease (PD). It is not known, however, which cellular elements (neurons or glial cells) are major targets of oxygen-mediated damage. 4-Hydroxy-2-nonenal (HNE) was shown earlier to react with proteins to form stable adducts that can be used as markers of oxidative stress-induced cellular damage. We report here results of immunochemical studies using polyclonal antibodies directed against HNE-protein conjugates to label the site of oxidative damage in control subjects (ages 18-99 years) and seven patients that died of PD (ages 57-78 years). All the nigral melanized neurons in one of the midbrain sections were counted and classified into three groups according to the intensity of immunostaining for HNE-modified proteins--i.e., no staining, weak staining, and intensely positive staining. On average, 58% of nigral neurons were positively stained for HNE-modified proteins in PD; in contrast only 9% of nigral neurons were positive in the control subjects; the difference was statistically significant (Mann-Whitney U test; P < 0.01). In contrast to the substantia nigra, the oculomotor neurons in the same midbrain sections showed no or only weak staining for HNE-modified proteins in both PD and control subjects; young control subjects did not show any immunostaining; however, aged control subjects showed weak staining in the oculomotor nucleus, suggesting age-related accumulation of HNE-modified proteins in the neuron. Our results indicate the presence of oxidative stress within nigral neurons in PD, and this oxidative stress may contribute to nigral cell death.

[The relationship between visual agnosia and visual pathway for perception].

We report a patient with a unique visual agnosia, who was thought to have lost visual functions except for the primary visual function. The patient was a 71-year-old woman with progressive memory loss and cerebro-cortical atrophy in MRI; her clinical diagnosis was senile dementia of Alzheimer's type. A battery of tests to detect higher visual dysfunctions was performed. First of all, we presented small dots and lines in front of the patient; the patient was able to recognize them. When a triangle, a tetragon, a cube, pieces of paper of different colors and lines of different length were presented, she was unable to recognize those objects. When pictures of her family members or filled circles of different size including small dots and lines were presented, the patient could only detect those small dots and any of lines; she could not recognize the members of her family. The cerebral blood flow was severely reduced in the occipital lobe except for the striate cortex. These data suggested that the visual function of striate cortex was preserved in this patient; the disturbance of higher visual functions was thought to be caused by the dysfunction of extra striate cortex.

[Clinical and neuroradiological studies on orbital myositis and Tolosa-Hunt syndrome].

Tolosa-Hunt syndrome and orbital myositis have common features such as ocular pain, ophthalmoplegia and exophthalmos. Both syndromes are thought to be caused by a granulomatous inflammation involving the cavernous sinus area in the former and the orbital cavity in the latter. The question whether these two conditions represent different presentations of a single disease, or they belong to different entities has not been settled. To address this question, we reviewed our cases having clinical diagnosis of either Tolosa-Hunt syndrome or orbital myositis. Six cases were diagnosed as Tolosa-Hunt syndrome, and 7 orbital myositis. In the thin-slice enlarged orbital CT, hypertrophic and high-density changes of at least one of the extraocular muscles were found in all cases with orbital myositis, but in none of the patients with Tolosa-Hunt syndrome. The age of onset was younger and the duration of the disease before admission was shorter in Tolosa-Hunt syndrome. They responded to steroid therapy better than those with orbital myositis. These findings lead us to conclude that Tolosa-Hunt syndrome and orbital myositis belong to different syndromes, although clinical manifestations have many similarities. Then we studied the relationship between the hypertrophic change of the extraocular muscle and the direction of the oculomotor restriction. For this purpose four additional cases with dysthyroid ophthalmopathy were also studied. We found that the presence of hypertrophic change was frequently associated with the restriction of ocular movement to the direction not only of the hypertrophic muscle but also of the opposite muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

[A case of solitary thalamic abscess treated by sterotactic aspiration].

The Solitary thalamic abscess appears to be uncommon, 17 cases have been reported since 1973. We successfully treated a case of thalamic abscess associated with diabetes mellitus by sterotactic aspiration with external drainage. A 55 years old man presented right hemiparesis. A computed tomographic (CT) scan revealed solitary thalamic low density lesion with ringed contrast enhancement. We started the administration of antibiotics, but on the 9th day he became drowsy and his eyes were deviated downward and inward. CT scan on the 10th day showed the edema had been spread to the tectum. We aspirated purulent fluid material with confidence by sterotactic operation. We considered the mid brain tectum to be responsible for the downward and medial deviation of the eyes, because it appeared only when the edema and abscess were spread to that area, and disappeared after aspiration of the abscess with subsidence of the edema.